Comparison of transarterial chemoembolization with drug-eluting beads in combination with apatinib versus transarterial chemoembolization with drug-eluting beads for the treatment of unresectable hepatocellular carcinoma: a randomized, prospective, multicenter phase III trial

Participant

This phase III, multicenter, randomized, open-label study was conducted in 12 hospitals in China from January 2021 to June 2022. The uHCC diagnosis was based on the guidelines “Diagnostic and therapeutic criteria for primary liver cancer” in China.⁴² Consider biopsy, cytology, or diagnostic imaging (dynamic computed tomography or magnetic resonance imaging). Participants with uHCC were randomly assigned to DEB-TACE alone (DEB-TACE) and DEB-TACE + apatinib groups in a 1:1 ratio by computer-assisted central randomization using permuted blocks (sizes four and six).

The main eligibility criteria were: 1) uHCC patients with histopathologically or cytologically confirmed recurrence/metastasis who strictly met the clinical diagnostic criteria of the “Diagnostic and therapeutic criteria for primary liver cancer” (2017 edition) were not eligible for palliative surgery or radiotherapy and had ≥1 measurable lesion based on the mRECIST criteria, indicating a long diameter of ≥10 mm the lesion required measurable or a short diameter ≥15 mm for the enlarged lymph node); 2) after liver cancer was confirmed, no treatments were performed before DEB-TACE, such as: B. immunotherapy, liver transplant, surgical resection, cTACE, radiofrequency/microwave/chemical ablation, argon-helium knife, ultrasonic scalpel, radiation therapy, systemic chemotherapy and targeted therapies, e.g. B. sorafenib, renfatinib, apatinib and PD-1, programmed death ligand 1 (PD-L1) and cytotoxic inhibitors of T lymphocyte-associated protein 4 (CTLA-4); 3) BCLC stage BC and non-diffuse liver cancer; 4) age 18 to 75 years; 5) Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1 within 1 week prior to enrollment; 6) liver tumor, which accounts for 4 copies/ml); 10) negative pregnancy test in women of childbearing potential within 7 days prior to enrollment; and 11) signing the informed consent to participate in the study and good compliance.

Exclusion criteria were: 1) Imaging examination showed that the HCC liver tumor was huge (≥60% of the liver volume) or tumor thrombus in the main portal vein (vessel diameter ≥50%), mesenteric vein or inferior vena cava was invasive or obviously arteriovenous Fistula; 2) a history of liver transplantation, surgical resection, TACE, radiofrequency/microwave/chemical ablation, argon-helium knife, ultrasonic scalpel, radiotherapy or other local treatments or systemic chemotherapy, oral targeted liver cancer drugs (sorafenib, renfatinib or apatinib). ) or immunotherapy such as PD-1/PD-L1/CTLA-4; 3) diffuse liver cancer, known cholangiocarcinoma, mixed cell carcinoma or fibrolamellar cell carcinoma, previously detected (1.5 or prothrombin time (PT) > ULN + 4 s), with bleeding tendency or under thrombolytic or anticoagulant treatment; 7) Central nervous system or brain metastases, previous and currently confirmed pulmonary fibrosis, interstitial pneumonia, radiation pneumonitis, drug-related pneumonia, severe pulmonary dysfunction, HIV infection, pregnant or lactating women, or planned liver transplant (except for patients). with previous liver transplant); 8) expected operating system

DEB TACE

A standardized DEB-TACE was administered to all participants at each participating institution. The tumor-supplying artery was typically identified using hepatic angiography using the Seldinger puncture technique and abdominal trunk arteriography. Access to the artery supplying the tumor was achieved using microcatheters using superselective catheterization. CalliSpheres (Jiangsu Hengrui Pharmaceutical, China) containing 40–60 mg of doxorubicin or epirubicin (100–300 or 300–500 μ m ) were administered slowly by injection into the tumor-feeding artery following previously described techniques.^20.21 In case of incomplete embolization, additional 350–560 μm polyvinyl alcohol (PVA) particles (Hangzhou Alikang Pharmaceutical Technology, Zhejiang, China) or 300–500 μm microspheres (Jiangsu Hengrui Pharmaceutical) could be used.

Interventional radiologists with ≥10 years of experience performed all TACE sessions at each participating center. Intravenous analgesia, a combination of dexmedetomidine and dezocine, was administered for 48 hours from the start of TACE to relieve pain during the procedure. After DEB-TACE, participants received 3-5 days of liver protection and symptomatic treatments to treat embolic syndrome symptoms. DEB-TACE was used in case of disease progression or a condition that makes DEB-TACE infeasible (e.g. tumor thrombus in the main artery trunk or vascular injury), or in persistent liver dysfunction, e.g. B. Child-Pugh score ≥9 points persistent over a longer period of time, discontinued 4 weeks.

Systemic therapy

Apatinib (Jiangsu Hengrui Pharmaceutical, Co., Ltd., Shanghai, China) was administered orally for the first time to participants in the DEB-TACE + apatinib group 3–5 days after DEB-TACE, initially at 500 mg once daily. Apatinib administration was stopped 3 days before a subsequent TACE session. In cases where participants experienced grade ≥3 adverse reactions, the apatinib dose was reduced to 250 mg once daily, suspended, or discontinued. The maximum duration of apatinib suspension was two weeks, with no more than two suspensions allowed. If symptomatic treatment did not alleviate the observed adverse reactions, discontinuation of apatinib was considered. Participants who tolerated AEs at 250 or 500 mg once daily continued apatinib until tumor progression, intolerance, or death.

Assessment of the effectiveness of treatment

After the initial TACE procedure, participants underwent routine blood analysis, assessment of liver and kidney function, assessment of coagulation function and detection of tumor markers, as well as enhanced magnetic resonance imaging (MRI) and/or computed tomography (CT) four to six weeks later. . Two experienced radiologists evaluated the scans using mRECIST criteria to determine curative effects (best response), ie, complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD). The analysis based on RECIST 1.1 was used for sensitivity analysis. ORR and DCR were obtained as CR + PR and CR + PR + SD, respectively. PFS was calculated from the date of the first TACE to disease progression or death, and OS from the first TACE to death or last follow-up. Subsequent TACE procedures were performed if the tumor maintained arterial blood supply according to enhanced MRI and/or CT with confirmed Child-Pugh classification A/B. Treatment continued until untreatable progression defined by meeting DEB-TACE refractoriness criteria, intolerable toxicity, or withdrawal of consent. During the embolization process of DEB-TACE, embolization with drug-loaded microspheres can create new spaces within the tumor mass, resulting in the accumulation of contrast agents. This imaging manifestation appears as an early arterial phase with slow disappearance, and the contrast agent may still accumulate up to the venous phase and resemble a vascular lake.

Follow-up and safety assessments

Complications associated with DEB-TACE included fever, nausea, vomiting, abdominal pain, constipation, ascites, liver abscesses, and hepatic artery thinning and spasm during the second DEB-TACE procedure. Apatinib-related side effects, e.g. B. Hypertension, hand-foot syndrome, fatigue, diarrhea, gastrointestinal reactions and liver dysfunction were treated by symptomatic treatment. The screened participants or their families were interviewed about side effects, survival status, and cause of death (if reported) after treatment through outpatient visits, WeChat, and/or mobile phone communication. Adverse events were documented using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 (NCI-CTCAE 4.03).

After three or more consecutive standardized and refined TACE treatments, an enhanced CT/MRI examination 1-3 months after the last procedure showed that the intrahepatic target lesion was still in a state of disease progression compared to before the first TACE treatment ( PD) TACE resistance was considered according to the mRECIST criteria. In such cases, it was necessary to immediately rule out further TACE and switch to other treatments.

Sample size estimation

The primary endpoint was PFS. Based on previous reports and clinical experience,^40,44,45 The estimated median PFS for DEB-TACE + apatinib was approximately 9 months, compared to approximately 6 months for DEB-TACE. The statistical parameters set for the test were: two-sided class I error probability (α), 0.05; beta (β), 0.2; Performance: 0.8. The aim of the study was a ratio of 1:1 in both treatment groups. The PASS software calculated that a minimum of 117 and 116 participants were required in the DEB-TACE + apatinib and DEB-TACE groups, respectively, allowing for a potential loss to follow-up of 5–15%. Therefore, the total sample size for both treatment groups was 233 participants.

Statistical methods

Continuous variables were presented as mean ± standard deviation and analyzed using Student's t test. Categorical variables were analyzed using the chi-square test or Fisher exact test for comparison. Liver and kidney functions were analyzed using repeated measures analysis of variance. Kaplan-Meier curves were used to analyze survival outcomes, with differences assessed by the log-rank test. Factors affecting OS and PFS were assessed by univariable and multivariable Cox proportional hazard regression analyzes and the results were expressed as hazard ratios with corresponding confidence intervals. The center effect was considered random due to the inclusion conditions of this study (12 centers in total, some of which had a limited number of participants). Given the data type (survival data) and the need for adjustment for random effects, a Cox frailty model was used to adjust for the center effect, and the enrollment center was included as a random intercept.⁴⁶